Pharmacodynamic Evaluation of the ANTICALCIURIC Effect of Hydrochlorothiazide in Dent's Disease

Intrarenal calcifications (nephrocalcinosis) is present in Dent's disease and likely contribute to progression toward renal failure. In order to prevent this complication it is usually proposed to treat affected patients during childhood with high doses of thiazides. Indeed, this class of diuretics is used for years to treat hypertension, can lower urinary calcium excretion. However the doses usually used are high, are known to be associated with adverse events such as severe potassium depletion, decrease in blood pressure and dehydration. The purpose of the study was to test whether lower dose of thiazides would be better tolerated, with similar efficacy to lower urinary calcium excretion, as previously demonstrated in other indication such as treatment of hypertension.

Patient recruitment and clinical evaluation Eight subjects with genetically proven Dent's disease were recruited through a French nationwide network for tubulopathies and were enrolled between July 2003 and December 2005.

All patients met at least three standard criteria for the disease including hypercalciuria, low molecular weight proteinuria and one of the following disorders: nephrocalcinosis, nephrolithiasis, renal failure, aminoaciduria, glucosuria, renal phosphate wasting, or familial history of Dent's disease. The disease was confirmed in all patients by direct sequencing of the CLCN5 gene according to Lloyd et al. (25) Patients presenting hyponatremia (< 135 mM), hypokalaemia (< 3.3 mM), severe fanconi syndrome, or chronic renal failure (GFR estimated with the Schwartz formula < 30 mL.min-1.1.73m-2) were excluded from the study.

The protocol was approved by the "comité de protection des personnes" (Paris, Hôtel Dieu) and all subjects and/or their parents gave written informed consent for the participation in the study.

Sodium restriction test Because a renal loss of sodium was reported in the disease, the pharmacological study was preceded by a sodium restriction test involving NaCl intake equivalent to 0.3 mmol/kg BW) and an age-adjusted calcium intake of 1200-1500 mg/day, to assess the tolerance to sodium depletion and its effect on calcium excretion. Sodium restriction was stopped after 5 days or when 24h urinary sodium excretion matched theoretical salt intake. Blood and urine samples were taken in the morning, two hours after a light calcium-free breakfast and after a 30 minute rest in the supine position on the first and last days of the low sodium diet determining electrolytes, plasma proteins, hematocrit, and plasma renin and aldosterone concentrations.